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. 2024 Nov;279(Pt 4):135455.
doi: 10.1016/j.ijbiomac.2024.135455. Epub 2024 Sep 10.

Screening and modification of (+)-germacrene A synthase for the production of the anti-tumor drug (-)-β-elemene in engineered Saccharomyces cerevisiae

Yuhan Hu  1 , Qin Zhang  2 , Xue Bai  2 , Lianhui Men  2 , Jing Ma  2 , Dengyu Li  2 , Mengdie Xu  2 , Qiuhui Wei  3 , Rong Chen  4 , Daming Wang  3 , Xiaopu Yin  5 , Tianyuan Hu  6 , Tian Xie  7
Affiliations

Screening and modification of (+)-germacrene A synthase for the production of the anti-tumor drug (-)-β-elemene in engineered Saccharomyces cerevisiae

Yuhan Hu et al. Int J Biol Macromol. 2024 Nov.

Abstract

(-)-β-Elemene is a primary bioactive compound derived from Curcuma wenyujin and has been widely utilized as an anti-tumor agent for various types of cancer. Due to the inefficiency of plant extraction methods for β-elemene, significant efforts have been directed toward the heterogeneous biosynthesis of β-elemene using microbial cell factories. However, there has been less emphasis on the stereochemical configuration of germacrene A and its rearranged product, β-elemene. In this study, we constructed a yeast cell factory to produce (-)-β-elemene by optimizing the mevalonate pathway and screening for germacrene A synthases (GASs) from both plant and microbial sources. Notably, we discovered that the rearranged products of GASs exhibited different conformations, and only (+)-germacrene A produced by plant-derived GASs could rearrange to form (-)-β-elemene. Building on this discovery, we further investigated the catalytic mechanisms of GASs and developed an efficient catalytic gene module for generating (+)-germacrene A. Ultimately, the engineered yeast produced 1152 mg/L of (-)-β-elemene, marking the highest titer reported in yeast to date. Overall, this work highlights the differences in the stereoconformations of catalytic products between plant- and microbial-derived germacrene A synthases and establishes a foundation for the green and efficient production of β-elemene with a specific stereochemical configuration.

Keywords: Biosynthesis; Germacrene A synthase; Saccharomyces cerevisiae; β-Elemene.

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Conflict of interest statement

Declaration of competing interest The authors declare no conflicts of interest.

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